IL-15 and IL-2 are members of the 4alpha-helix bundle family of cytokines. Heterotrimeric receptors for both cytokines on lymphocytes share the same constitutively expressed pair of signal transducing subunits. IL-2 and IL-15 can bind the dimeric IL-2/15Rbeta,gammac receptor and transmit intracellular signals. To differentiate signals by IL-15 and IL-2, "private" accessory alpha subunits (IL-15Ralpha and IL-2Ralpha) are expressed forming trimeric receptors that confer specificity for each cytokine. Whereas numerous studies have documented various actions of IL-2 in the CNS such as its neuromodulatory and neurotrophic actions in septal and hippocampal neurons, the neural and immunological actions of IL-15 in the brain are largely unknown. Several lines of evidence have led investigators to hypothesize that functional effects ascribed to endogenous IL-2 may well be attributable to endogenous IL-15. Moreover, in the immune system these cytokines have both shared and distinctly different actions. Of particular relevance to the studies outlined in this proposal, IL-15 is powerful T-cell chemoattractant, a characteristic not shared by IL-2. Although studies have implicated IL-2 signaling through IL-2/15Rbeta,gammac in the hippocampal formation and related limbic regions, the effects of IL-15 on these neurons is unknown and will be examined in the proposed studies. In the brain, some classical immune cytokines have been found to have neuromodulatory and neurotrophic effects that are limited to very specific neural pathways, while exerting more general effects on the brain's endogenous immune cells (e.g., microglia). We postulate that IL-15 also has this characteristic. Recent observations including our preliminary data suggest that the IL- 15/IL-15R system may orchestrate interactions between T- lymphocytes, microglia and regenerating neurons following axotomy. Using this model in the proposed studies, we will test the hypothesis that IL-15 plays a key role in neuronal regeneration. Thus, the proposed Specific Aims will: 1) test the hypothesis that IL-15Ralpha and IL-15 are enriched in the hippocampus and related limbic regions, and are expressed by neurons; 2) determine which neuromodulatory and neurotrophic effects of IL-15 on septal and hippocampal neurons are different from those of IL-2, and; 3) test the hypothesis that glial- derived IL-15 plays an essential role in motor neuron regeneration following nerve axotomy.